Because of the importance of the nervous system in disease manifestations caused by scrapie, we will pursue detailed investigation of neuronal infection with a variety of scrapie agents. We will use a cloned pheochromocytoma cell line, termed PC12, as an in vitro neuronal model to study scrapie. This cell line, in the continued presence of nerve growth factor (NGF). undergoes morphological differentiation and attains many of the biochemical and physiological properties of neurons. In addition, NGF-treated PC12 cells has been shown to support 139A scrapie agent replication. Two major issues will be addressed in this proposal. The first focuses on how the metabolic state of the neuron determines the character of scrapie agent infection. Specific aspects to be investigated include the influence on the course of infection of: the developmental maturity of neurons, the route of viral spread, the effect of trophic factors, and the activity state of the neuron. The objective of these studies will be to determine whether these extraneural influences alter the course of infection. The second issue to be studied is how the physiology and metabolism of neurons is altered during scrapie infection. We will execute detailed investigations of how infection perturbs polypeptide and glycoprotein synthesis, catecholamine and acetylcholine neurotransmitter metabolism, glucose utilization, selected membrane properties, axonal transport, and polyamine metabolism. These studies will provide a better understanding of the scrapie agent-host cell interaction and the potential to investigate the role of similar agents in Senile Dementia of the Alzheimer's Type and other CNS disorders of unknown etiology.